Faculty Bibliography

BACKGROUND: Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI). METHODS AND RESULTS: Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1 x 10(5) (low-dose) and 9 to 1 x 10(6) (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration. CONCLUSIONS: This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00616980.

BACKGROUND: : Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately. OBJECTIVE: : To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs. METHODS: : Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease. RESULTS: : Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%). CONCLUSION: : Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality. ABBREVIATION:: AVM, arteriovenous malformation.